Orientador: José Reinaldo Cerqueira Braz / Resumo: Os anestésicos inalatórios halogenados podem apresentar papel importante na patogênese das alterações cardiocirculatórias e renais durante o choque hemorrágico por alterarem, de maneira dose dependente, os mecanismos de defesa compensatórios. O presente estudo teve como objetivo comparar os efeitos de uma concentração alveolar mínima (CAM) de halotano, sevoflurano e isoflurano sobre o sistema cardiovascular e renal em cães submetidos a choque hemorrágico e reposição volêmica com o sangue retirado do animal. O estudo aleatório foi realizado em trinta cães, sem raça definida, distribuídos em três grupos de acordo com o anestésico inalatório halogenado utilizado durante a anestesia, em concentrações eqüipotentes de uma CAM: GH (n=10) - halotano a 0,89%; GS (n=10) - sevoflurano a 2,4%; e GI (n=10) - isoflurano a 1,4%. Todos os cães foram ventilados mecânicamente, esplenectomizados e submetidos a sangramento, com retirada em torno de 40% do volume sangüíneo, visando manter a pressão arterial média de 40 a 50 mm Hg durante 45 minutos. A seguir, os cães foram submetidos à expansão volêmica com o sangue removido. Os atributos hemodinâmicos foram determinados no momento controle, após 45 minutos de hemorragia, e 15 e 60 minutos após a reposição sangüínea. Os atributos renais foram medidos nos mesmos momentos, exceto no período hemorrágico, pela ausência de diurese. No momento controle, a maioria das variáveis hemodinâmicas e renais foram semelhantes entre os grupos, com exceção da fração de filtração, cujos valores foram menores no grupo GI, em relação aos grupos GH e GS (p < 0,05), e da osmolalidade urinária, cujos valores foram maiores no grupo GS, em comparação com o grupo GH (p < 0,05). Após a hemorragia ...(Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Halogenated anesthetics may play an important role in the pathogenesis of cardiovascular and renal changes during hemorrhagic shock because they modify, in a dose-dependent manner, compensatory defense mechanisms. The aim of the present study was to compare the effects of a minimum alveolar concentration (MAC) of halothane, sevoflurane and isoflurane on the cardiovascular and renal systems of dogs subjected to hemorrhagic shock followed by restoration of blood volume with shed blood. Thirty mongrel dogs were randomly distributed into three groups according to the halogenated anesthetic used for anesthesia. They were anesthetized with halothane (H group; n=10), sevoflurane (S group; n=10) or isoflurane (I group; n=10) and anesthesia was maintained at 1.0 MAC: 0.89%, 2.4%, and 1.4%, respectively. All the dogs were mechanically ventilated, splenectomized and subjected to bleeding with 40% blood reduction to keep mean arterial pressure between 40 and 50 mm Hg for 45 min. Thereafter, the dogs were resuscitated with shed blood. The hemodynamic attributes were determined at the control moment, after 45 min of hemorrhage, 15 and 60 min after restoration of blood volume. The renal attributes were determined at the described moments, except during the hemorrhage period, for lack of diuresis. At the control moment, most of the hemodynamic and renal variables were similar among the groups, except for the filtered fraction, Introdução e Literatura 11 which was lower in GI than in groups GH and GS (p < 0.05), and for urinary osmolarity, which was higher in GS compared to GH (p < 0.05). After hemorrhage, the hemodynamic attributes decreased, without significant differences among the groups (p > 0.05). Fifteen minutes after resuscitation, most of the hemodynamic and renal attributes were... (Complete abstract click electronic access below) / Doutor

Orientador: Carmen Sílvia Bertuzzo / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-23T04:59:08Z (GMT). No. of bitstreams: 1 Assis_AngelaMariade_D.pdf: 2409399 bytes, checksum: 620279a2d72b5132a10f7af956d4bebf (MD5) Previous issue date: 2007 / Resumo: A Telangiectasia Hemorrágica Hereditária (THH) é uma desordem autossômica dominante caracterizada por epistaxe recorrente, telangiectases mucocutânea, hemorragia gastrointestinal, e malformação arteriovenosa pulmonar (PAVM), cerebral e hepática. A prevalência da doença é de 1/5000 e a mortalidade relatada da doença entre pacientes jovens quando comparado com aqueles com mais de 60 anos é de 36%. Dois genes da superfamília de receptores para TGF-? têm sido relacionados com THH, o gene da endoglina e o gene da activina (activin receptor-like-kinase). Estes genes são altamente expressos em células endoteliais e outros tecidos altamente vascularizados como pulmão e placenta. Mutações no gene da endoglina causam a THH tipo 1 que é caracterizada pela alta incidência de malformação arteriovenosa pulmonar sintomática (PAVMs). Mutações no gene da activina levam a THH tipo 2 caracterizada por epistaxe recorrente e malformação arteriovenosa gastrointestinal. Foi objetivo deste trabalho realizar uma triagem de mutações na região codificadora dos genes ALK-1 e endoglina em doze pacientes portadores de THH atendidos no Hemocentro da Unicamp. A abordagem metodológica incluiu a amplificação dos exóns dos genes da activina e endoglina seguida pela técnica de PCR/CSGE, clonagem e sequenciamento. Dos doze pacientes estudados, sete apresentaram alguma alteração molecular, destes três pacientes apresentaram uma deleção de um nucleotídeo T na posição 913 no exon 7, um paciente apresentou uma inserção de um nucleotídeo G na posição 204-205 no exon 3 e três pacientes apresentavam uma mutação misense nos exons 7 e 8 na posição 976 e 1204 respectivamente. Nossos resultados mostraram que a THH tipo 1 e tipo 2 são raras no Brasil e todas as mutações citadas na tabela IV e Figura 10 são novas, somente a mutação ocorrida no exon 8 foi previamente descrita na literatura / Abstract: Background: Hereditary hemorrhagic telangiectasia in humans, also known as HHT or Osler-Rendu-Weber syndrome, is an autosomal dominant vascular disorder characterizes by recurrent epistaxis, mucocutaneous telangiectases, gastrointestinal, pulmonary, cerebral and hepatic arteriovenous malformations (HAVM). The prevalence of the illness is of 1/5000 and the reported mortality of the illness among young patients when compared with those with more than 60 years is 36%. Two genes of the receptors superfamily for TGF-? have been related with THH, the gene of the endoglin (ENG) in the chromosome 9q33-34 and the gene of the activin (receptor-like-kinase 1 ALK-1), in the chromosome 12q11q14. These genes are highly express in endothelial cells and other tissue highly vascularized as lung and placenta. Mutations in the gene of the endoglin cause the HHT type 1 which is characterized by the high incidence of symptomatic pulmonary arteriovenous malformation (PAVM). Mutations in the activin gene cause HHT were described among patients in whom the linking with HHT in the chromosome 9q33 or mutation in the endoglin gene was excluded. It was the objective of this work to carry through a selection of mutations in the coding region of gene ALK-1 and endoglin in 12 patients carrying HHT whose are treated in the Blood Center at Unicamp. Methods: Twelve patients were analyzed. Diagnosis of HHT was carried out by means of clinical history of recurrent bleeding, heredity studies, and the presence of multiple telangiectases lesions. PCR products with consistent abnormal migration patterns were cloned into the SureCloneTM ligation kit vector system and sequenced using the DYEnamic TM ET dye terminator cycle sequencing Kit, and analyzed by the MegaBace 1000 DNA automated analyzer. A panel of 252 chromosomes from unrelated individuals without the disease was used to evaluate the frequency of each mutation in the general population. Results: In six patients three novel mutations were identified in the coding sequence of the ALK-1 gene in their families, which demonstrated clinical manifestations of HHT type 2. These mutations included an insertion a deletion of single base pairs in éxons 3 (c.204-205insG) and 7 (c.913del T), as well as missense mutations in éxons 7 (c.976A>G) and 8 (c.1204G>A) of the ALK-1 gene. The mutations identified in éxons 7 and 8 affect the kinase domain and the mutation identified in éxon 3 affect the extracellular domain. These data indicate that loss-of-function mutations in a single allele of the ALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity. Conclusion: We suggest the high rate of mutation detection and the small size of the ALK-1 gene make genomic sequencing a viable diagnostic test for HHT2. This was the only research about this subject made in Brazil so far / Doutorado / Genetica Animal e Evolução / Doutora em Genética e Biologia Molecular

No description available.

Patients with atrial fibrillation (AF) are at increased risk of stroke. Warfarin anticoagulation therapy reduces the incidence of stroke and increases the incidence of hemorrhagic events. This dissertation further informs the decision to use anticoagulation therapy in AF patients by examining outcomes in patients with major hemorrhages, further examination of stroke risk in diabetic patients with AF, and by evaluating the association between warfarin and stroke while accounting for competing risk events. These studies utilized data from the AnTicoagulation and Risk Factors In Atrial Fibrillation (ATRIA) and ATRIA-CVRN (Cardiovascular Research Network) (Study 1 only) studies which consist of patients from Kaiser Permanente Northern and Southern California. Study 1 examined short and long-term mortality in patients who experienced major gastrointestinal (GI) hemorrhages. In the ATRIA cohort, patients using and not using warfarin at the time of GI hemorrhage were equally likely to die within 30-days, while in ATRIA-CVRN, patients using warfarin were much less likely to die within 30-days (adjusted mortality rate ratio (aMRR): 0.33, 95% CI: 0.16-0.70). For longer-term mortality, both cohorts were consistent with a reduced mortality rate among patients whose GI hemorrhage occurred while using warfarin. Study 2 assessed the association between diabetes characteristics (duration of diabetes and glycemic control) and incidence of ischemic stroke among patients with AF and diabetes. Duration ≥ 3 years was associated with a large increase in rate of stroke (adjusted hazard ratio (aHR): 2.04, 95% CI: 1.27-3.26) compared to patients with duration < 3 years. Patients with the poorest glycemic control (hemoglobin A1c (HbA1c) values ≥ 9.0%) did not have an increased rate of ischemic stroke compared to patients with HbA1c < 7.0%. Study 3 evaluated the association between warfarin and thromboembolism in analyses that did and did not account for competing death events. In analyses not accounting for competing events, the adjusted HR was 0.61 (95% CI: 0.54-0.69), and after accounting for competing death events this association was attenuated (aHR: 0.87, 95% CI: 0.77-0.99). In summary, these studies add to the literature about the benefits of warfarin therapy and risk of stroke in patients with AF, findings that can improve decisions about use of anticoagulants in patients with AF.

京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第21693号 / 医科博第97号 / 新制||医科||7(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 中川 一路, 教授 朝長 啓造, 教授 西渕 光昭 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves [98]-118).

Le virus de la fièvre hémorragique de Crimée-Congo (VFHCC) est un Nairovirus appartenant à la famille des Bunyaviridae, responsable d’une maladie hémorragique sévère chez l’Homme, associée à des symptômes non spécifiques et à une forte mortalité. La transmission se fait par morsure de tique ou par contact direct avec des fluides corporels contaminés. N’ayant ni vaccin ni traitement spécifique, un apport de connaissances sur les interactions cellulaires VFHCC-hôte ainsi que sur les mécanismes développés en réponse à l’infection est nécessaire.Nous avons tout d’abord étudié le potentiel antiviral de molécules sur la réplication du VFHCC. La chloroquine et la chlorpromazine ont été identifiées et inhibent efficacement la réplication virale avec une protection induite chez la souris contre l’infection, en particulier en combinaison avec la ribavirine.De nombreux virus sont connus pour être ciblés par, ou pour détourner la voie de l’autophagie. Nous avons regardé si l’infection par le VFHCC était associée à une modulation de l’autophagie et si la réplication virale était impactée par l’activité autophagique. L’étude de cellules hépatocytaires et épithéliales a montré une mobilisation massive du LC3, principal marqueur des vésicules autophagiques, par le VHFCC. Celle-ci reflète une induction du flux autophagique d’un nouveau type, n’impliquant pas les voies classiques de recrutement du LC3. La réplication virale n’est pas directement modulée par cette autophagie atypique mais des effets indirects sont à étudier. La plupart de ces observations ont été montrées pour le Nairovirus Dugbe avec cependant une cinétique différente.Le dernier axe étudié porte sur l’analyse de l’impact des IFITMs, facteurs de restriction virale connu pour interférer avec les processus de fusion membranaire, sur la réplication du virus Dugbe. L’étude a révélé une inhibition de la réplication virale par certains IFITMs.Des études supplémentaires portant sur l’interaction virus-cellule hôte et les mécanismes moléculaires associés sont nécessaires pour mieux comprendre la physiopathologie induite par le VFHCC et mettre au point de nouvelles stratégies thérapeutiques. / Crimean-Congo hemorrhagic fever virus (CCHFV) belongs to Nairovirus genus and to Bunyaviridae family. It is responsible for a severe hemorrhagic disease in humans, associated with non-specific symptoms and high lethality. Transmission is made by tick’s bite or by direct contact with contaminated body fluids. Since no vaccines or treatments are available, there is a need to accumulate knowledge on all aspects of CCHFV-host cell interaction as well as on response mechanisms that are taking place during infection.We first investigated pharmacological ways to interfere with CCHFV replication. Chloroquine and chlorpromazine (known modulators of some viral infections) were efficiently inhibiting viral replication and induce a protection in mice against CCHFV infection, particularly in the presence of ribavirin. Since several viruses are targeted by, or take advantage of, the autophagy response of infected cells, we explored whether CCHFV infection was associated with modulation of autophagy and whether virus replication was impacted by the autophagic activity of infected cells. By using hepatocytes and epithelial cells, we found that CCHFV induced a massive mobilization of the major marker of autophagic vesicles LC3. This mobilization reflected an induced autophagy flux and was of a novel type since known pathways of LC3 recruitment were not involved. The replication of CCHFV was indeed not directly modulated by this atypical form of autophagy but indirect effects remain to be studied. Most of these observations were found to be valid for the related, Dugbe virus (DUGV) with however, a distinct kinetic.Finally, we analyzed whether DUGV was sensitive to the IFITMs, restriction factors that can interfere with membrane fusion processes. Studies revealed that DUGV replication could be inhibited by some IFITMs. Additional studies on virus host-cell interactions and their associated molecular mechanisms should help to better understand the physiopathology induced by CCHFV and to devise therapeutic strategies.

Kyasanur Forest disease virus (KFDV) of the Flaviviridae virus family has caused seasonal infections and periodic outbreaks in Karnataka, India. First identified in 1957, KFDV annually infects 400-500 people and has a fatality rate of 3-5%; there are no approved antivirals and the existing licensed vaccine’s effectiveness appears to be questionable. Many tools for KFDV research are limited and this work sought to develop methods for analysing antivirals, including interferon (IFN)-α/β species. The BHK-21 (ATCC) cell line allowed for high virus propagation and distinguishable cytopathic effects (CPE) for determining antiviral effectiveness. The additional tool of a reverse genetics system expressing a full-length cDNA KFDV genome with a GFP reporter failed to propagate, despite numerous GFP genome-insertion strategies. The clinically approved IFN-α2a or IFN-α2b has had variable success at combatting flavivirus diseases in people, especially in the immuno-compromised. The continued passaging of KFDV-infected cells with repeated IFN-α2a treatment did not eliminate KFDV and had little effect on infectious particle production. IFN-αspecies, αWA and α were more effective than IFN-α2a and α2b at reducing KFDV; however dose ranges indicated that while low concentrations could limit CPE, higher concentrations were needed to inhibit virion release. Avoidance of IFN-α/β through Jak/STAT signalling repression was attributed to the NS5 protein, specifically the RdRp domain based on data obtained with luciferase and vesicular stomatitis virus (VSV) recovery assays. However, the mechanism appears to act subsequently to STAT1/2 activation without NS5 binding to any Jak/STAT components. A non-infectious, replicative system serving as a platform for antiviral drug testing against KFDV in a high throughput manner could only provide luciferase signals when the NS proteins capable of driving replication, were supplied in cis (subgenomic) but not in trans (antigenome). To conclude, IFN-α species such as IFN-αWA may be better suited than the licensed IFN-α2a for treatment of KFDV infections; however, IFN effects appear to be subdued in vitro due to the actions of the NS5 protein. While IFN may not be a successful antiviral against KFDV, the work in this thesis provides a foundation for evaluating other potential anti-KFDV therapeutics. / February 2016

Over the last 20 years, much work has focused on computer-aided clinical decision support systems due to a rapid increase in the need for management and processing of medical knowledge. Among all fields of medicine, trauma care has the highest need for proper information management due to the high prevalence of complex, life-threatening injuries. In particular, hemorrhage, which is encountered in most traumatic injuries, is a dominant factor in determining survival in both civilian and military settings. This complication can be better managed using a more in-depth analysis of patient information. Trauma physicians must make precise and rapid decisions, while considering a large number of patient variables and dealing with stressful environments. The ability of a computer-aided decision making system to rapidly analyze a patient’s condition can enable physicians to make more accurate decisions and thereby significantly improve the quality of care provided to patients. The first part of this study is focused on classification of highly complex databases using a hierarchical method which combines two complementary techniques: logistic regression and machine learning. This method, hereafter referred to as Classification Using Significant Features (CUSF), includes a statistical process to select the most significant variables from the correlated database. Then a machine learning algorithm is used to identify the data into classes using only the significant variables. As the main application addressed by CUSF, a set of computer-assisted rule-based trauma decision making system are designed. Computer aided decision-making system not only provides vital assistance for physicians in making fast and accurate decisions, proposed decisions are supported by transparent reasoning, but also can confirm a physicians’ current knowledge, enabling them to detect complex patterns and information which may reveal new knowledge not easily visible to the human eyes. The second part of this study proposes an algorithm based on a set of novel wavelet features to analyze physiological signals, such as Electrocardiograms (ECGs) that can provide invaluable information typically invisible to human eyes. These wavelet-based method, hereafter referred to as Signal Analysis Based on Wavelet-Extracted Features (SABWEF), extracts information that can be used to detect and analyze complex patterns that other methods such as Fourier cannot deal with. For instance, SABWEF can evaluate the severity of hemorrhagic shock (HS) from ECG, while the traditional technique of applying power spectrum density (PSD) and fractal dimension (FD) cannot distinguish between the ECG patterns of patients with HS (i.e. blood loss), and those of subjects undergoing physical activity. In this study, as the main application of SABWEF, ECG is analyzed to distinguish between HS and physical activity, and show that SABWEF can be used in both civilian and military settings to detect HS and its extent. This is the first reported use of an ECG analysis method to classify blood volume loss. SABWEF has the capability to rapidly determine the degree of volume loss from hemorrhage, providing the chance for more rapid remote triage and decision making.